Histological efficacy of anti-diabetic agents in MASH and the mediating role of weight loss: A network meta-analysis.

BACKGROUND: Metabolic dysfunction-associated steatohepatitis (MASH) is a progressive liver disease with rising global prevalence, closely linked to type 2 diabetes. While several anti-diabetic agents show promise, a comprehensive analysis comparing their efficacy on biopsy-confirmed histological outcomes, including dose-dependent effects and the mediating role of weight loss, remains unexplored. METHODS: A frequentist random-effects network meta-analysis (NMA) was conducted to explore histological efficacy of anti-diabetic agents in biopsy-confirmed MASH without cirrhosis. The primary outcome was fibrosis improvement (≥1 stage) without worsening steatohepatitis; the secondary outcome was MASH resolution without fibrosis worsening. Incretin-based agents were dose-stratified. Treatment ranking used surface-under the cumulative-ranking curve (SUCRA). Meta-regression investigated the impact of percentage weight loss and baseline covariates on the proportion of individuals achieving histological end-points. RESULTS: Data from five RCTs (N = 1667) were included. All active treatments, including Dapagliflozin 10 mg, Survodutide (2.4 mg/wk, 4.8-6 mg/wk), Tirzepatide (5 mg/wk, 10-15 mg/wk), and Semaglutide (0.7-1.4 mg/wk, 2.4 or 2.8 mg/wk), improved fibrosis versus placebo (I = 0%). For MASH resolution, dose-dependent effects led to significant heterogeneity (I = 73%), with lower-dose Semaglutide demonstrating no benefits and Dapagliflozin showing benefits in the F2-F3 subgroup only on sensitivity analysis. Survodutide exhibited the highest ranking (SUCRA = 0.822-0.849), followed by Tirzepatide (SUCRA = 0.622-0.681) and higher-dose Semaglutide (SUCRA = 0.327) for MASH resolution. Meta-regression using data from 16 interventions, including placebo arms, showed that weight loss significantly explained heterogeneity in treatment effects on fibrosis improvement (R = 54.26%) and MASH resolution (R = 78.16%). CONCLUSIONS: SGLT2 inhibitor and incretin-based agents improved fibrosis in MASH, with weight loss being a significant mediator. Targeting multiple incretin pathways, especially involving glucagon receptors, may offer greater MASH resolution. Dose-dependent effects were more prominent for MASH resolution than fibrosis improvement, indicating potential weight-loss-independent anti-fibrotic pathways.